TY - JOUR
T1 - Circadian rhythms in CYP2A5 expression underlie the time-dependent effect of tegafur on breast cancer
AU - Yoshida, Yuya
AU - Fukuda, Taiki
AU - Tanihara, Tomohito
AU - Nishikawa, Naoki
AU - Iwasa, Serina
AU - Adachi, Satoka
AU - Zaitsu, Orion
AU - Terada, Yuma
AU - Tsukamoto, Ryotaro
AU - Shimoshikiryo, Hideki
AU - Fukuoka, Kohei
AU - Tsurusaki, Fumiaki
AU - Hamamura, Kengo
AU - Oyama, Kosuke
AU - Tsuruta, Akito
AU - Koyanagi, Satoru
AU - Matsunaga, Naoya
AU - Ohdo, Shigehiro
N1 - Publisher Copyright:
© 2024 Elsevier Inc.
PY - 2024/5/14
Y1 - 2024/5/14
N2 - The chemotherapeutic agent tegafur, a prodrug that prolongs the half-life of fluorouracil (5-FU), exerts antitumor effects against various cancers. Since tegafur is metabolized to 5-FU by CYP2A6 in the liver, the expression of CYP2A6 determines the effect of tegafur. Here, we report that the expression rhythm of Cyp2a5, a homolog of human CYP2A6, in female mice causes dosing time-dependent differences in tegafur metabolism. In the livers of female mice, CYP2A5 expression showed a circadian rhythm, peaking during the dark period. This rhythm is regulated by RORA, a core clock component, and abrogation of the CYP2A5 activity abolished the time-dependent difference in the rate of tegafur metabolism in female mice. Furthermore, administration of tegafur to mice transplanted with 4T1 breast cancer cells during the dark period suppressed increases in tumor size compared to female mice treated during the light period. Our findings reveal a novel relationship between 5-FU prodrugs and circadian clock machinery, potentially influencing antitumor effects, and contributing to the development of time-aware chemotherapy regimens for breast cancer.
AB - The chemotherapeutic agent tegafur, a prodrug that prolongs the half-life of fluorouracil (5-FU), exerts antitumor effects against various cancers. Since tegafur is metabolized to 5-FU by CYP2A6 in the liver, the expression of CYP2A6 determines the effect of tegafur. Here, we report that the expression rhythm of Cyp2a5, a homolog of human CYP2A6, in female mice causes dosing time-dependent differences in tegafur metabolism. In the livers of female mice, CYP2A5 expression showed a circadian rhythm, peaking during the dark period. This rhythm is regulated by RORA, a core clock component, and abrogation of the CYP2A5 activity abolished the time-dependent difference in the rate of tegafur metabolism in female mice. Furthermore, administration of tegafur to mice transplanted with 4T1 breast cancer cells during the dark period suppressed increases in tumor size compared to female mice treated during the light period. Our findings reveal a novel relationship between 5-FU prodrugs and circadian clock machinery, potentially influencing antitumor effects, and contributing to the development of time-aware chemotherapy regimens for breast cancer.
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U2 - 10.1016/j.bbrc.2024.149813
DO - 10.1016/j.bbrc.2024.149813
M3 - Article
C2 - 38522403
AN - SCOPUS:85188710212
SN - 0006-291X
VL - 708
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
M1 - 149813
ER -